Biotransformation Flashcards
Consequences of biotransformation
activation of pro-drug
active compound–>active compound
inactivation
Sites of biotransformation
liver mainly
also GI, lungs, skin, kidneys
What is the first-pass effect
oral drugs absorbed in SI–>liver–> hepatic portal system-> extensive metabolism
***limits bioavailability of some drugs
What drugs have bioavailability increased via GI flora?
estrogens used in contraception d/t recycling of metabolites
What is an example of a drug that undergoes extensive first pass biotransformation and only 25% reaches blood?
morphine
Is phase 1 of metabolism catabolic or anabolic
catabolic–>inactivates drug via unmasking functional group to make it polar
Where are phase 1 enzymes located
lipophilic ER membranes of liver
What is the function of phase 2
conjugate–>more excretable
ex: glucuronidation
anabolic
What phase do CYPs work in
phase 1
What CYP is involved in 50% drug metabolism
CYP 3A4
What CYPs are most important
1A2
2A6
2D6
2E1
3A4
Where do CYPs get their reducing power
NADPH (use O2 and H to oxidize drugs and make polar)
Genetic defect in pseudocholinesterase has what effect
metabolize succinylcholine 50% the rate as normal people
Why can AR trait, which has decrease in N-acetyltransferase, cause hepatotoxicity?
caffeine, isoniazid, hydralazine metabolized at slower rates since less enzyme–> builds up in liver and causes hepatitis
What enzymes are involved in phase 1
CYPs
FMO
hydrolases
What are phase 2 enzymes
transferases
Inducer examples
phenobarbital
chronic ethanol
tobacco smoke (aromatic hydrocarbons)
rifampin
St John’s wort
What do inducers do to drug levels
activate enzymes, so less drug in body
What happens to clearance with inducers?
inducers decrease half-life, so clearances increases
Prominent inhibitors
grapefruit juice
allopurinol and mercaptopurine given together–> increases merc. toxicity
What is the grapefruit juice effect
grapefruit with drugs can irreversibly inhibit CYP 3A4
What makes neonates highly susceptible to drug toxicity
underdeveloped BBB, weak biotransforming activity, immature excretion
What is the most important factor for decreased drug metabolism in elderly
liver and kidney disease
not really drug dependent d/t half-life
Give example of biotransformation to toxic product
acetaminophen-induced hepatotoxicity
intake exceeds therapeutic dose, GSH in liver is depleted faster than regenerated–> toxic metabolites accumulate
Explain polymorphism in CYP 2D6
codeine–> morphine (200 x agonist) normally
if polymorphism, insufficient pain relief and increased risk for side effects (resp depression, drowsiness)
Explain polymorphism in CYP 2C 19
decreases active metabolite formation and reduces Clopidogrel’s antiplatelet activity
–> severe risk for cardiovascular events
Explain polymorphism in G6PD
hemolysis when using drugs for lowering uric acid
Phase 0
microdosing to human volunteers
Phase 1
25-50 people
aware what testing is being conducted
absorption, half life, metabolism
Phase 2
100-200 people
single blind (physician knows)
placebo, dosing requirements, efficacy, toxicities
Phase 3
300-3000 people
safety
crossover and double blind
Phase 4
after market approval
monitor in population
